IL133142A - Pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent - Google Patents

Pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent

Info

Publication number
IL133142A
IL133142A IL133142A IL13314299A IL133142A IL 133142 A IL133142 A IL 133142A IL 133142 A IL133142 A IL 133142A IL 13314299 A IL13314299 A IL 13314299A IL 133142 A IL133142 A IL 133142A
Authority
IL
Israel
Prior art keywords
compound
pharmaceutically acceptable
metformin
diabetes mellitus
acceptable form
Prior art date
Application number
IL133142A
Other languages
Hebrew (he)
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26311745&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IL133142(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GBGB9712857.3A external-priority patent/GB9712857D0/en
Priority claimed from GBGB9806706.9A external-priority patent/GB9806706D0/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Publication of IL133142A publication Critical patent/IL133142A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Description

A PHARMACEUTICAL COMPOSITION FOR TREATING DIABETES MELLITUS COMPRISING AN INSULIN SENSITIZER AND A BIGUANIDE ANTIHYPERGLYCAEMIC AGENT This invention provides a pharmaceutical composition for the treatment of diabetes especially dependent diabetes or Type II diabetes and conditions associated diabetes Biguanide antihyperglycaemic agents are commonly used in the of Type II 1 Dimethylbiguanidine is an example of a biguanides ant yperglycaemic European Patent Publication Number relates to certain thiazoiidinedione derivatives disclosed as having antihypergiycaemic and hypolipidaemic One particular thiazoiidinedione disclosed in EP 0306228 is discloses certain salts of Compound including salt at example 1 thereof Compound is an example of a class of agents known as particular Compound is a thiazoiidinedione insulin European Patent Publication 0332331 International Patent Publication Numbers 93 22445 and United States Patent Numbers 5104888 and also disclose certain thiazoiidinedione insulin series of compounds generally recognised as having sensitiser activity are those typified by the compounds disclosed in International Patent Publication Numbers and These compounds are herein referred to as insulin Other examples of acyclic insulin sensitisers are those disclosed in United States Patent Number 5232945 and International Patent Publication Numbers and Examples of other insulin sensitisers are those disclosed in European Patent Publication Number Japanese Patent Application Publication Number 05271204 and United States Patent Number above mentioned publications are incorporated herein by It is now surprisingly indicated Compound in combination with a biguanide antihyperglycaemic agent provides a particularly beneficial effect on glycaemic control with no observed adverse such combination is therefore particularly useful for the treatment of diabetes especially Type II diabetes and conditions associated with diabetes Accordingly the present invention provides a combination which comprises from 2 to 8 mg of or a pharmaceutically acceptable form and up to 3000 mg of metformin or metformin In one the combination comprises from 2 to 4 or 4 to 8 mg of Compound or a pharmaceutically acceptable form the combination comprises from 2 to 4 mg of Compound or a pharmaceutically acceptable form the combination comprises from 4 to 8 mg of Compound or a pharmaceutically acceptable form the combination comprises 2 mg of Compound or a pharmaceutically acceptable form the combination comprises 4 mg of Compound or a pharmaceutically acceptable form the combination comprises 8 mg of Compound or a pharmaceutically acceptable form the combination of the present invention comprises 500 mg or 850 mg of metformin or metformin the combination is one wherein Compound or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as a single pharmaceutical the combination is one wherein Compound or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as separate pharmaceutical Most the combination of the present invention is for the treatment of diabetes mellitus or a condition associated with diabetes The treatment using a combination of the present invention comprises either of Compound or a pharmaceutically acceptable form and metformin or metformin hydrochloride or the sequential administration includes administration of a formulation which includes both Compound or a pharmaceutically acceptable form and metformin or metformin or the essentially simultaneous administration of separate formulations of each In another aspect the present invention provides use of from 2 to 8 mg of or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use in the treatment of diabetes mellitus or a condition associated with diabetes the present invention provides use of from 2 to 8 mg of or a pharmaceutically acceptable form thereof in the manufacture of a medicament for use with up to 3000 mg of metformin or metformin hydrochloride in the treatment of diabetes mellitus or a condition associated with diabetes Still further the present invention provides use of up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use with from 2 to 8 mg of dione or a pharmaceutically acceptable form thereof in the treatment of diabetes mellitus or a condition associated with diabetes It will be understood that Compound is administered in a pharmaceutically acceptable including pharmaceutically acceptable derivatives such as pharmaceutically acceptable esters and solvates as It will be understood that all pharmaceutically acceptable forms of the active agent per se are encompassed by this Suitable pharmaceutically acceptable forms of Compound include those described in EP 0306228 and especially pharmaceutically acceptable salted A preferred pharmaceutically acceptable salt is a Suitable pharmaceutically acceptable forms of Compound include those described in EP 0306228 and in particular Compound or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate may be prepared using known for example those disclosed in EP 0306228 and The disclosures of EP 0306228 and are incorporated herein by Compound may exist in one of several tautomeric all of which are encompassed by the term Compound as individual tautomeric forms or as mixtures Compound contains a chiral carbon and hence can exist in up to two stereoiosmeric the term Compound encompasses all of these isomeric forms whether as individual isomers or as mixtures of including Compound pharmaceutically acceptable forms metformin and metformin hydrochloride are prepared according to known such methods are found or referred to in standard reference such as the British and US Pharmaceutical Sciences Publishing Martindale The Extra Pharmacopoeia The Pharmaceutical example see the 31st Edition on page 341 and pages cited or as described in the mentioned When used herein the term associated with diabetes1 includes conditions associated with the conditions associated with diabetes itself and complications associated with diabetes When used herein the term associated with the inchides conditions soch as including hereditary impaired tolerance and associated with diabetes meilitus itself include including acquired resistance and Further conditions associated with diabetes mellitns itself include hypertension and cardiovascular especially atherosclerosis and conditions associated with Conditions associated with resistance include polycystic ovarian syndrome and steroid induced resistance and gestational associated with diabetes includes renal especially renal disease associated with Type Π neuropathy and Renal diseases associated with Type Π diabetes include glomerular nephrotic hypertensive nephrosclerosis and end stage renal As used herein the term pharmaceutically embraces both human and veterinary for example the term embraces a acceptable For the avoidance of when reference is made herein to scalar mcfcdmg mg of Compound in a pharmaceutically acceptable the scalar amount referred to is mack m of Compound example 2 mg of Compound in the form of the salt is that amount of maleate salt which contains 2 mg of Compound Diabetes is preferably Type H The particnlariy beneficial effect on glycaemic control provided by the treatment of the invention is indicated to be a synergistic effect relative to the control expected for the sum of the effects of the active Glycaemic control may be characterised using conventional for example by measurement of a typically used index of glycaemic control such as fasting plasma glucose or glycosylated haemoglobin Such indices are determined using standard for example those described Tuescher 101 and 390 and the Diabetic Patent with Glycosolated Hemoglobin Clinical Products a preferred the dosage level of each of the active agents when used in accordance the treatment of the invention be less than would have been required a purely additive effect upon glycaemic is also indication that the treatment of the invention effect an relative to the individual the levels of advanced end products leptin and lipids including total choIesteroL mcluding improvements in the ratios in particular in Epids including total H cholesteroL including improvements in the ratios thereof The active medicaments are preferably adrrxinistered in pharmaceutical composition As indicated such compositions can include both medicaments or one only of the in one aspect of the invention there is provided a pharmaceutical composition comprising from 2 to 8 mg of a pharmaceutically acceptable form up to 3000 mg of metformin or metformin hydrochloride and a pharmaceutically acceptable carrier said composition is for use in the treatment of diabetes mellitus or a condition associated with diabetes Such compositions may be prepared by admixing from 2 to 8 mg of Compound or a pharmaceutically acceptable form metformin or hydrochloride and a pharmaceutically acceptable carrier therefor Usually the compositions are adapted for oral they may be for other modes of for example parenteral or transdermal The compositions may be in the form of or liquid such as oral or sterile parenteral solutions or In order to obtain consistency of administration it is preferred that a composition of the invention is in of a unit Unit doss forms oral may be tablets and capsules and may contain conventional such as for example or for example calcium sorbitol or tabletiing for example magnesium for example sodium starch glycoUate or rmcrociystalline or pharinaceuti acceptable wetting agents such as sodium The compositions preferably a unit dosage form in an appropriate the relevant daily Suitable unit dosages of the Compound of formula comprise 7 8 of Compound The composition of the invention may be administered 1 to 6 times a but most preferably 1 or 2 times per Particular dosages of Compound are are 2mg twice per and S mg 4mg twice per Suitable dosages of metfonnin or metformin hydrochloride include up to 3000mg per in unit doses of 500mg example two or three times per or 850mg example two times per one example of a dosage for metformin is once building to five times per one example of of combination of the present invention is 4 or 8mg of Compound 2mg twice per day or 4mg twice per day and lOOOmg or 2500mg of metformin 500mg twice per day or 500mg five times per day The oral compositions may be prepared by conventional methods of filling or Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of Such of course conventional in the The tablets may be coated to methods known in normal in particular with an enteric Oral liquid preparations may be in the form for or or may be presented as a dry product for with water or other suitable vehicle before Such liquid preparations may contain conventional additives such as suspending for example methyl hydrogenated edible emulsifying example sorbftan or vehicles may include edible for example almond fractionated coconut oily esters such as esters of propylene or ethyl for example or propyl or sorbic and if desired conventional flavouring or colouring For parenteral fluid unit dosage forms are prepared the compound and a sterile depending on the can be either suspended or dissolved in the In preparing solutions the can be dissolved in for injection and filter sterilized before into a suitable or ampoule and adjuvants such as a local a preservative and buffering agents can be dissolved in the To enhance the the composition can be frozen after filling into the vial and the removed under Parenteral are prepared in substantially the except that the Compound suspended in the vehicle of being and sterilization cannot be accomplished by The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the Compositions may contain from to by preferably from by of the active depending upon the method of Compositions if be in the form of a pack accompanied by written printed instructions for The compositions are formulated according to conventional such as those disclosed in standard reference for example the British and US Sciences Publishing Martindale The Extra Pharmacopoeia The Pharmaceutical example see the st Edition page 341 and pages cited and A range of 2 to 4mg includes a range of to to 23 to to to to to to to 4 or 3 to A range of 4 to 8mg includes a range of to to 43 to to to to to to to 5 to to 8 7 to No adverse effects have been established for the compositions or methods of the invention in the abovementioned dosage Tbe following example the invention but does not ft any Example This study evaluated the pharmacokinetics of Compound and metformin administered alone and in Sixteen male aged 22 to 55 received Compound mg Q mg or each for 4 Plasma collected on day 4 of each regimen was assayed for Compound and Oral doses of Compound and M were safe and well tolerated alone or in There were no episodes of hypoglycemia and did not result in an increase in blood lactic acid Combo Compound Coadministration of Compound and did not affect the pharmacokinetics or of either Because M plasma concentrations coadministration or Compound not accentuate the dependent toxicities of COMPOUND COMPOSITIONS A Concentrate Preparation Approximately two thirds of the lactose monohydrate is passed through a suitable screen and blended with the milled maleate salt of Compound Sodium starch cellulose and the remaining lactose are passed through a suitable screen and added to the Blending is then The respiting mixture is then wet granulated with purified The wet granules are then dried on a fluid bed drier and the dried granules are passed through a further screen and finally COMPOSITION OF CONCENTRATE Ingredient Quantity Milled Compound as maleate salt maleate Starch Hydoxypropyl 2910 e Cellulose Lactose regular to 100 grade Purified water Removed during B Formulation of the concentrate into The granules above are placed into a tumble Approximately two thirds of the lactose is screened and added to the The sodium starch magnesium stearate and remaining lactose are screened and added to the blender and the mixture blended The mix then compressed on a rotary tablet press to a target weight of 150mg for the 1 2 and 4mg tablets and to a target weight of 300mg for the Smg The tablet cores are then to a tablet coating with warm air 65 and film coated the tablet weight has increased by to Tablet Strength Active Compound grannies Other Starch Macrocrystalline Cellulose Lactose Magnesium Stearate 150 Total Weight of Tablet Aqueous coaling material 4 Total Weight of Coated Tablet insufficientOCRQuality

Claims (17)

133142/3 -12- CLAHviS
1. A combination which comprises from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)ammo)ethoxy]berizyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof, and up to 3000 mg of metformin or metformin hydrochloride.
2. A combination according to claim 1, which comprises from 2 to 4 or 4 to 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.
3. A combination according to claim 1 or claim 2, which comprises from 2 to 4 mg of Compound (I) or a pharmaceutically acceptable form thereof.
4. A combination according to claim 1 or claim 2, which comprises from 4 to 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.
5. A combination according to any one of claims 1 to 3, which comprises 2 mg of Compound (Γ) or a pharmaceutically acceptable form thereof.
6. A combination according to any one of claims 1 to 4, which comprises 4 mg of Compound (I) or a pharmaceutically acceptable form thereof.
7. A combination according to any one of claims 1, 2 and 4, which comprises 8 mg of Compound (I) or a pharmaceutically acceptable form thereof.
8. A combination according to any one of claims 1 to 7, which comprises 500 mg or 850 mg of metformin or metformin hydrochloride.
9. A combination according to any one of claims 1 to 8, wherein compound (I) is in the form of its maleate salt. 133142/3 -13-
10. A combination according to any preceding claim, wherein Compound (I) or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as a single pharmaceutical composition.
11. A combination according to any one of claims 1 to 9, wherein Compound (Γ) or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride are formulated as separate pharmaceutical compositions.
12. A combination according to any one of claims 1 to 11 for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.
13. A pharmaceutical composition comprising from 2 to 8 mg of 5-[4-[2-(N-memyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof, up to 3000 mg of metformin or metformin hydrochloride and a pharmaceutically acceptable carrier therefor.
14. A pharmaceutical composition according to claim 13 for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.
15. Use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof and up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.
16. Use of from 2 to 8 mg of 5-[4-[2-(N-methyl-N-(2-pyridyl)ammo)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (1)) or a pharmaceutically acceptable form thereof in the manufacture of a medicament for use with up to 3000 mg of metformin or metformin hydrochloride in the treatment of 133142/3 -14-diabetes mellitus or a condition associated with diabetes mellitus.
17. Use of up to 3000 mg of metformin or metformin hydrochloride in the manufacture of a medicament for use with from 2 to 8 mg of 5-[4-[2-(N-methyI-N-(2-pyridyl)ammo)emoxy]beiizyl]thiazolidine-2,4-dione (Compound (I)) or a pharmaceutically acceptable form thereof in the treatment of diabetes mellitus or a condition associated with diabetes mellitus.
IL133142A 1997-06-18 1999-11-25 Pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent IL133142A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9712857.3A GB9712857D0 (en) 1997-06-18 1997-06-18 Novel method of treatment
GBGB9806706.9A GB9806706D0 (en) 1998-03-27 1998-03-27 Novel method
PCT/EP1998/003690 WO1998057634A1 (en) 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin

Publications (1)

Publication Number Publication Date
IL133142A true IL133142A (en) 2006-06-11

Family

ID=26311745

Family Applications (3)

Application Number Title Priority Date Filing Date
IL13314298A IL133142A0 (en) 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin
IL133142A IL133142A (en) 1997-06-18 1999-11-25 Pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent
IL173650A IL173650A0 (en) 1997-06-18 2006-02-09 A pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent

Family Applications Before (1)

Application Number Title Priority Date Filing Date
IL13314298A IL133142A0 (en) 1997-06-18 1998-06-15 Treatment of diabetes with thiazolidinedione and metformin

Family Applications After (1)

Application Number Title Priority Date Filing Date
IL173650A IL173650A0 (en) 1997-06-18 2006-02-09 A pharmaceutical composition for treating diabetes mellitus comprising an insulin sensitizer and a biguanide antihyperglycaemic agent

Country Status (39)

Country Link
US (3) US20060100247A1 (en)
EP (2) EP0996444B1 (en)
JP (1) JP2002504137A (en)
KR (2) KR100666591B1 (en)
CN (2) CN1230171C (en)
AP (1) AP1279A (en)
AR (2) AR012995A1 (en)
AT (1) ATE355840T1 (en)
AU (1) AU8539398A (en)
BG (2) BG64818B1 (en)
BR (1) BR9810172A (en)
CA (1) CA2294582C (en)
CY (2) CY1107643T1 (en)
CZ (1) CZ298469B6 (en)
DE (2) DE122007000054I1 (en)
DK (1) DK0996444T3 (en)
DZ (1) DZ2520A1 (en)
EA (1) EA003144B1 (en)
ES (1) ES2284212T3 (en)
HK (1) HK1028193A1 (en)
ID (1) ID23372A (en)
IL (3) IL133142A0 (en)
IN (1) IN189722B (en)
LU (1) LU91356I2 (en)
MA (1) MA26512A1 (en)
MY (1) MY129897A (en)
NL (1) NL300288I2 (en)
NO (4) NO324993B1 (en)
NZ (1) NZ501260A (en)
OA (1) OA11516A (en)
PE (1) PE83199A1 (en)
PL (2) PL195140B1 (en)
PT (1) PT996444E (en)
SI (1) SI0996444T1 (en)
SK (1) SK286029B6 (en)
TR (1) TR199903057T2 (en)
TW (1) TW565449B (en)
UY (1) UY25049A1 (en)
WO (1) WO1998057634A1 (en)

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